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Temperature‐induced changes in dissociation constants (K A ) of agonists at cardiac β‐adrenoceptors determined by use of the irreversible antagonist Ro 03–7894
Author(s) -
Broadley Kenneth J.,
Williams Russell G.
Publication year - 1983
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.1983.tb11026.x
Subject(s) - chronotropic , orciprenaline , isoprenaline , dissociation constant , chemistry , medicine , inotrope , endocrinology , agonist , guinea pig , atrium (architecture) , antagonist , receptor , heart rate , biochemistry , blood pressure , atrial fibrillation , stimulation
1 The positive inotropic responses of guinea‐pig left atria and papillary muscles and positive chronotropic responses of right atria to sympathomimetic amines were examined at 38° and 30°C. 2 At the lower temperature, supersensitivity to orciprenaline and isoprenaline was exhibited as shifts of the dose‐response curves to the left and significant reductions in EC 50 values. 3 This supersensitivity could not be attributed to reduced metabolism since the experiments were performed in the presence of metanephrine (10 −5 m ) and U‐0521 (3×, 4×‐dihydroxy‐2‐methylpropiophenone) (10 −4 m ) as inhibitors of extraneuronal uptake and catechol‐ O ‐methyltransferase (COMT) respectively, and the agonists are not susceptible to neuronal uptake. 4 After incubation of the tissues with Ro 03–7894 (1‐(5‐chloracetylaminobenzfuran‐2‐yl)‐2‐isopropylaminoethanol), followed by its prolonged washout (> 2h), the maximum responses to isoprenaline and orciprenaline were depressed, confirming the apparently irreversible β‐adrenoceptor antagonism. 5 Dissociation constants (K A ) for isoprenaline and orciprenaline were determined from the equiactive concentrations obtained before (A) and after (A′) incubation with Ro 03–7894, plotted as 1/A against 1/A′ ( K A = (slope — 1)/intercept). 6 K A values were the same for orciprenaline in the three cardiac preparations and for isoprenaline in the atria. This applied at 38° and 30°C and indicates that the β‐adrenoceptors mediating the inotropic and chronotropic responses of the guinea‐pig heart do not differ. 7 The K A values of both agonists were, however, consistently and significantly lower at 30° than at 38°C, indicating an increase in affinity. 8 It is concluded that hypothermia‐induced supersensitivity of cardiac tissue to sympathomimetic amines is associated with an increase in their affinity for the β‐adrenoceptors.